Download Aromatic Amino Acid Metabolism

I.
Phenylalanine and Tyrosine Biosynthesis
Sec. 22.2.4 Chorismate is a key Intermediate in the Synthesis of Tryptophan, Phenylalanine, and
Tyrosine
p. 8494/p. 8655
This section appears identical in editions 4 and 5 except for page numbers.
In this section, ignore the information on the synthesis of tryptophan from chorismate (Figs. 2217 and 22-18). Focus only on synthesis of phenylalanine and tyrosine (Figs. 22-16 and 22-19).
General Principles
• Amino acids are typically synthesized in "Families" from central metabolites
• The stereospecific reaction for synthesis of L-amino acids is usually transamination of an αketo acid.
• The benzene ring is synthesized from a linear poly-hydroxy chain by ring closure, followed by
introduction of double bonds (aromaticity) by dehydration reactions.
Step 6 in Fig. 22-16 (EPSP Synthase) is the target
of GLYPHOSATE, the active ingredient in the
herbicide widely marketed under the name
"ROUNDUP". Glyphosate is thought to act as an
inhibitor of EPSP because it is a transition state
analog of the PEP substrate.
The protonated nitrogen in glyphosate is analogous to the carbocation on the transition state.
Those of you who have a better recollection of O-Chem
than I may recognize that the conversion of
Chorismate to Prephenate (Step 1 in Fig. 22-19) is an
electrocyclic Diels-Alder Reaction. These are very
unusual in biochemistry.
STUDY QUESTIONS
The bacterium Klebsiella pneumoniae is capable of growing in a mineral salts medium in which
glucose is the only organic compound avasilable. Furthermore, K. pneumoniae is sensitive to
inhibition by glyphosate. What does this suggest about the metabolism of K. pneumoniae?
Mutants of K. pneumoniae that are resistant to glyphosate inhibition can be readily isolated.
These mutants have an altered gene for EPSP Synthase. The mutated, glyphosate-resistant EPSP
gene has been inserted into the genome of soybeans. What is the commercial incentive for doing
this?
Trace origin of the -OH group in the Tyr ring back to its origin in the precursors for the
biosynthtic pathway.
What exactly happen to this -OH in Phe biosynthesis?
Describe the reactions that introduce the chiral carbon atoms in Phe and Tyr biosynthesis.
Describe the reactions that introduce the nitrogen atoms in Phe and Tyr biosynthesis.
What is a transition state analog (TSA)? Give an example of a TSA that is an important drug.
II.
Catabolism of Aromatic Amino Acids
Sec. 18.3.4
Seven Amino Acids Are Degraded To Acetyl-CoA
p. 6774/p. 6955
Again, focus only on Phe and Tyr.
Sec. 18.3.5Phenylalanine Catabolism Is Genetically Defective In Some People
p. 6794/p. 6965
General Principles
Nearly all aromatic ring modification and cleavage in biochemistry requires oxygenases.
Oxygenases are extremely important in "xenometabolism".
OXYGENASES
Oxygenases are enzymes that catalyze reactions in which molecular oxygen is a substrate. The
O2 is reduced in the reaction by 4 electrons derived from one or more donor substrates, and one
or both oxygen atoms are incorporated in a product. All oxygenases are classified as
oxidoreductases.
Monooxygenases ("Mixed Function" Oxygenases)
C + O2 + reduced cofactor -----> C-OH + H2O + oxidized cofactor
2 of the necessary electrons are derived from a carbon atom in the princial substrate; the other
2 electrons are derived from one of several standard redox cofactors. The redox cofactor for
many monooxygenases is FMNH2, but the monooxygenases that participate in aromatic amino acid
metabolism the cofactor tetrahydrobioprerin (THBT) based on the pterin ring (Fig. 18-24). Note
that several of the monooxygenases involved in aromatic amino acid biosynthesis are referred to
as "hydroxylases".
Dioxygenases
C-C + O2 -----> HO-C-C-OH
Here, all 4 electrons are derived from the principal carbon substrate, so there is no redox
cofactor required.
STUDY QUESTIONS
What is the difference between a monooxygenase and a dioxygenase?
List all the oxygenase enzymes involved in aromatic amino acid modification and catabolism, and
identify each as a mono- or di- oxygenase.
Why is dietary restriction of phenylalanine intake not always a sufficient treatment, by itself,
for PKU? What additional dietary measures may be necessary, and why?
In the structure of Phe:
1. identify the carbon atom that is lost as CO2.
2. circle the carbons that enter the TCA Cycle as fumarate.
3. circle the carbons that enter the TCA Cycle as Acetyl-CoA.
List the "Inborn Errors of Metabolism" associated with Phe catabolism, and the defective enzyme
responsible for each.
One of the mono-oxygenases involved with aromatic amino acid metabolism uses a redox cofactor
other than FMNH2 or THBT. Draw the structures of the oxidized and reduced forms of this
cofactor.
Chapter 18 Problem #44/#115
III.
Secondary Products Made From Phe and Tyr
22.3.5 Aromatic Amino Acids are Precursors of Many Plant Substances
22.3.6 Biological Amines are Products of Amino Acid Decarboxylation
p. 8594/p. 8785
p. 8594/p. 8785
Again, in these sections we are interested in ONLY the information pertaining to Phe and Tyr (i.e.
only the LEFT panel of Fig. 22-9).
General Principles
The amino acids, and intermediates in amino acid biosynthesis, are frequently used as precursors
for important "secondary metabolites. Synthesis of these secondary metabolites is often
restricted to particular phylogenetic groups, and even to specific tisssues.
In this diagram, pathways restricted to animals are shown in blue. Green arrows show pathways
that may also found in plants and bacteria. Remember that the secondary metabolites in animals
must be synthesized from dietary amino acids.
Melanin Pigments
Gr. melas, melanos = "black"
Melanins are a family of brown,
yellow-brown, and red-brown pigments
found in many animals. They are high
molecular weight polymers whose
complexity and insolubility has
frustrated attempts to provide
definitive structural characterization.
They are synthesized from the amino
acid tyrosine (or from phenylalanine) via
L-DOPA, which is also the precursor for
several important neurotransmitters.
Melanins are found in both
invertebrates and vertebrates.
Examples include industrial melanism in the “peppered Moth” and other insects, the “ink” of squid,
and camouflage in flounder.
The functions ascribed to melanin include: cryptic coloration, signaling, and protection from
sunlight.
In vertebrates, melanins are synthesized in specialized cells derived from the neural crest called
melanocytes that invade the epidermis, the hair follicles, and the eye. Melanin is not uniformly
distributed throughout melanocytes, but is synthesized in specific sub-cellular granules called
melanosomes.
Melanosomes are transferred from melanocytes to
epidermal cells (keratinocytes) that will eventually
die and form the bulk of the epidermis and the hair
shaft. Melanocytes are also transferred to cells that
form the iris and the retina. Each melanocyte has
numerous long processes, or tubular extensions, that
allow each melanocyte to deliver melanosomes to as
many as several dozen keratinocytes. Ultimately,
keratinocytes may have higher melanin content than
melanocytes.
Variation in pigmentation is due largely to the
concentration of melanosomes in keratinocytes. This
is associated with the relative rates of melanosome synthesis and loss, and not to the number of
melanocytes, which is essentially uniform in all individuals.
As epidermal cells age, and move outwards, melanosomes may fuse with other organelles called
lysosomes, and this fusion brings about the destruction of melanosomes. Accordingly, cells of the
upper epidermis have decreased melanin content. Old, dead keratinocytes are eventually shed.
In the initial stages of melanosome synthesis, the melanosome is a fibrillar protein network with
tyrosine hydroxylase (and other enzymes?) attached. These unpigmented immature melanosomes
are frequently observed in albinos.